tbuckley/cabot-search huggingface dataset:
Chiropterans Are a Hotspot for Horizontal Transfer of DNA Transposons in Mammalia
Authors: Nicole S Paulat, Jessica M Storer, Diana D Moreno-Santillán, Austin B Osmanski, Kevin A M Sullivan, Jenna R Grimshaw, Jennifer Korstian, Michaela Halsey, Carlos J Garcia, Claudia Crookshanks, Jaquelyn Roberts, Arian F A Smit, Robert Hubley, Jeb Rosen, Emma C Teeling, Sonja C Vernes, Eugene Myers, Martin Pippel, Thomas Brown, Michael Hiller, Gregory Andrews, Joel C Armstrong, Matteo Bianchi, Bruce W Birren, Kevin R Bredemeyer, Ana M Breit, Matthew J Christmas, Hiram Clawson, Joana Damas, Federica Di Palma, Mark Diekhans, Michael X Dong, Eduardo Eizirik, Kaili Fan, Cornelia Fanter, Nicole M Foley, Karin Forsberg-Nilsson, Carlos J Garcia, John Gatesy, Steven Gazal, Diane P Genereux, Linda Goodman, Jenna Grimshaw, Michaela K Halsey, Andrew J Harris, Glenn Hickey, Michael Hiller, Allyson G Hindle, Robert M Hubley, Graham M Hughes, Jeremy Johnson, David Juan, Irene M Kaplow, Elinor K Karlsson, Kathleen C Keough, Bogdan Kirilenko, Klaus-Peter Koepfli, Jennifer M Korstian, Amanda Kowalczyk, Sergey V Kozyrev, Alyssa J Lawler, Colleen Lawless, Thomas Lehmann, Danielle L Levesque, Harris A Lewin, Xue Li, Abigail Lind, Kerstin Lindblad-Toh, Ava Mackay-Smith, Voichita D Marinescu, Tomas Marques-Bonet, Victor C Mason, Jennifer R S Meadows, Wynn K Meyer, Jill E Moore, Lucas R Moreira, Diana D Moreno-Santillan, Kathleen M Morrill, Gerard Muntané, William J Murphy, Arcadi Navarro, Martin Nweeia, Sylvia Ortmann, Austin Osmanski, Benedict Paten, Nicole S Paulat, Andreas R Pfenning, BaDoi N Phan, Katherine S Pollard, Henry E Pratt, David A Ray, Steven K Reilly, Jeb R Rosen, Irina Ruf, Louise Ryan, Oliver A Ryder, Pardis C Sabeti, Daniel E Schäffer, Aitor Serres, Beth Shapiro, Arian F A Smit, Mark Springer, Chaitanya Srinivasan, Cynthia Steiner, Jessica M Storer, Kevin A M Sullivan, Patrick F Sullivan, Elisabeth Sundström, Megan A Supple, Ross Swofford, Joy-El Talbot, Emma Teeling, Jason Turner-Maier, Alejandro Valenzuela, Franziska Wagner, Ola Wallerman, Chao Wang, Juehan Wang, Zhiping Weng, Aryn P Wilder, Morgan E Wirthlin, James R Xue, Xiaomeng Zhang, Danny Rojas, Liliana M Dávalos, Kerstin Lindblad-Toh, Elinor K Karlsson, David A Ray
Journal: Molecular Biology and Evolution (2023)

Abstract Horizontal transfer of transposable elements (TEs) is an important mechanism contributing to genetic diversity and innovation. Bats (order Chiroptera) have repeatedly been shown to experience horizontal transfer of TEs at what appears to be a high rate compared with other mammals. We investigated the occurrence of horizontally transferred (HT) DNA transposons involving bats. We found over 200 putative HT elements within bats; 16 transposons were shared across distantly related mammalian clades, and 2 other elements were shared with a fish and two lizard species. Our results indicate that bats are a hotspot for horizontal transfer of DNA transposons. These events broadly coincide with the diversification of several bat clades, supporting the hypothesis that DNA transposon invasions have contributed to genetic diversification of bats.
The Genetic Architecture of Adaptation to Leaf and Root Bacterial Microbiota in<i>Arabidopsis thaliana</i>
Authors: Fabrice Roux, Léa Frachon, Claudia Bartoli
Journal: Molecular Biology and Evolution (2023)

Understanding the role of the host genome in modulating microbiota variation is a need to shed light on the holobiont theory and overcome the current limits on the description of host-microbiota interactions at the genomic and molecular levels. However, the host genetic architecture structuring microbiota is only partly described in plants. In addition, most association genetic studies on microbiota are often carried out outside the native habitats where the host evolves and the identification of signatures of local adaptation on the candidate genes has been overlooked. To fill these gaps and dissect the genetic architecture driving adaptive plant-microbiota interactions, we adopted a genome-environment association (GEA) analysis on 141 whole-genome sequenced natural populations of Arabidopsis thaliana characterized in situ for their leaf and root bacterial communities in fall and spring, and a large range of nonmicrobial ecological factors (i.e., climate, soil, and plant communities). A much higher fraction of among-population microbiota variance was explained by the host genetics than by nonmicrobial ecological factors. Importantly, the relative importance of host genetics and nonmicrobial ecological factors in explaining the presence of particular operational taxonomic units (OTUs) differs between bacterial families and genera. In addition, the polygenic architecture of adaptation to bacterial communities was highly flexible between plant compartments and seasons. Relatedly, signatures of local adaptation were stronger on quantitative trait loci (QTLs) of the root microbiota in spring. Finally, plant immunity appears as a major source of adaptive genetic variation structuring bacterial assemblages in A. thaliana.
Irreversible electroporation augments β-glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma
Authors: Matthew R Woeste, Rejeena Shrestha, Anne E Geller, Shu Li, Diego Montoya-Durango, Chuanlin Ding, Xiaoling Hu, Hong Li, Aaron Puckett, Robert A Mitchell, Traci Hayat, Min Tan, Yan Li, Kelly M McMasters, Robert C G Martin, Jun Yan
Journal: Journal for ImmunoTherapy of Cancer (2023)

Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan induced trained immunity in the treatment of PC. β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag-/- mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral β-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral β-glucan after IRE was evaluated by mass cytometry. IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE. These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.
Severe cytopenia after CD19 CAR T-cell therapy: a retrospective study from the EBMT Transplant Complications Working Party
Authors: Olaf Penack, Christophe Peczynski, Christian Koenecke, Emmanuelle Polge, Andrea Kuhnl, Nathalie Fegueux, Michael Daskalakis, Nicolaus Kröger, Peter Dreger, Caroline Besley, Urs Schanz, Adrian Bloor, Arnold Ganser, Edouard Forcade, Lucia López Corral, Jakob R Passweg, Urban Novak, Ivan Moiseev, Hélène Schoemans, Grzegorz W Basak, Christian Chabannon, Anna Sureda, Dina Averbuch, Bertram Glass, Rafael de la Camara, Zinaida Peric
Journal: Journal for ImmunoTherapy of Cancer (2023)

We investigated the incidence and outcome of anti-CD19 chimeric antigen receptor (CAR) T-cells-associated Common Terminology Criteria for Adverse Events (CTCAE) ≥grade 3 cytopenia. In the EBMT CAR-T registry, we identified 398 adult patients with large B-cell lymphoma who had been treated with CAR-T-cells with axicel (62%) or tisacel (38%) before August 2021 and had cytopenia status documented for the first 100 days. Most patients had received two or three previous lines of therapy, however, 22.3% had received four or more. Disease status was progressive in 80.4%, stable in 5.0% and partial/complete remission in 14.6%. 25.9% of the patients had received a transplantation before. Median age was 61.4 years (min-max; IQR=18.7-81; (52.9-69.5)).The cumulative incidence of ≥grade 3 cytopenia was 9.0% at 30 days (95% CI (6.5 to 12.1)) and 12.1% at 100 days after CAR T-cell infusion (95% CI (9.1 to 15.5)). The median time from CAR-T infusion to cytopenia onset was 16.5 days (min-max; IQR=1-90; (4-29.8)). Grade 3 and grade 4 CTCAE cytopenia occurred in 15.2% and 84.8%, respectively. In 47.6% there was no resolution.Severe cytopenia had no significant impact on overall survival (OS) (HR 1.13 (95% CI 0.74 to 1.73), p=0.57). However, patients with severe cytopenia had a poorer progression-free survival (PFS) (HR 1.54 (95% CI 1.07 to 2.22), p=0.02) and a higher relapse incidence (HR 1.52 (95% CI 1.04 to 2.23), p=0.03). In those patients who developed severe cytopenia during the first 100 days (n=47), OS, PFS, relapse incidence and non-relapse mortality at 12 months after diagnosis of severe cytopenia were 53.6% (95% CI (40.3 to 71.2)), 20% (95% CI (10.4 to 38.6)), 73.5% (95% CI (55.2 to 85.2)) and 6.5% (95% CI (1.7 to 16.2)), respectively.In multivariate analysis of severe cytopenia risk factors, only year of CAR-T infusion (HR=0.61, 95% CI (0.39 to 0.95), p=0.028) and total number of treatment lines before CAR-T infusion (one or two lines vs three or more, HR=0.41, 95% CI (0.21 to 0.83), p=0.013) had a significant positive association with the incidence of cytopenia. Other factors, such as previous transplantation, disease status at time of CAR-T, patient age and patient sex, had no significant association.Our data provide insight on frequency and clinical relevance of severe cytopenia after CAR T-cell therapy in the European real-world setting.
Barriers to immune cell infiltration in tumors
Authors: Marit M Melssen, Natasha D Sheybani, Katie M Leick, Craig L Slingluff
Journal: Journal for ImmunoTherapy of Cancer (2023)

Increased immune cell infiltration into tumors is associated with improved patient survival and predicts response to immune therapies. Thus, identification of factors that determine the extent of immune infiltration is crucial, so that methods to intervene on these targets can be developed. T cells enter tumor tissues through the vasculature, and under control of interactions between homing receptors on the T cells and homing receptor ligands (HRLs) expressed by tumor vascular endothelium and tumor cell nests. HRLs are often deficient in tumors, and there also may be active barriers to infiltration. These remain understudied but may be crucial for enhancing immune-mediated cancer control. Multiple intratumoral and systemic therapeutic approaches show promise to enhance T cell infiltration, including both approved therapies and experimental therapies. This review highlights the intracellular and extracellular determinants of immune cell infiltration into tumors, barriers to infiltration, and approaches for intervention to enhance infiltration and response to immune therapies.
BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors
Authors: Yu Fu, Bin Yang, Yaoyuan Cui, Xingyuan Hu, Xi Li, Funian Lu, Tianyu Qin, Li Zhang, Zhe Hu, Ensong Guo, Junpeng Fan, Rourou Xiao, Wenting Li, Xu Qin, Dianxing Hu, Wenju Peng, Jingbo Liu, Beibei Wang, Gordon B Mills, Gang Chen, Chaoyang Sun
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Mismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers. Methods We confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry. Results We identified the positive correlation between BRD4 and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance. Conclusions We demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.
Serum lipidome unravels a diagnostic potential in bile acid diarrhoea
Authors: Monika Lewinska, Martin Lund Kårhus, Anne-Marie Gade Ellegaard, Manuel Romero-Gómez, Rocio I R Macias, Jesper B Andersen, Filip Krag Knop
Journal: Gut (2023)

Bile acid diarrhoea (BAD) is debilitating yet treatable, but it remains underdiagnosed due to challenging diagnostics. We developed a blood test-based method to guide BAD diagnosis.
Consensus definition of sludge and microlithiasis as a possible cause of pancreatitis
Authors: Michal Żorniak, Simon Sirtl, Georg Beyer, Ujjwal Mukund Mahajan, Katharina Bretthauer, Jörg Schirra, Christian Schulz, Thomas Kohlmann, Markus M Lerch, Julia Mayerle
Journal: Gut (2023)

Objective In up to 20% of patients, the aetiology of acute pancreatitis (AP) remains elusive and is thus called idiopathic. On more detailed review these cases can often be explained through biliary disease and are amenable to treatment. Findings range from biliary sludge to microlithiasis but their definitions remain fluid and controversial. Design A systematic literature review (1682 reports, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines) analysed definitions of biliary sludge and microlithiasis, followed by an online international expert survey (30 endoscopic ultrasound/hepatobiliary and pancreatic experts; 36 items) which led to definitions of both. These were consented by Delphi voting and clinically evaluated in a retrospective cohort of patients with presumed biliary pancreatitis. Results In 13% of original articles and 19.2% of reviews, microlithiasis and biliary sludge were used synonymously. In the survey, 41.7% of experts described the term ‘sludge’ and ‘microlithiasis’ as identical findings. As a consequence, three definitions were proposed, agreed on and confirmed by voting to distinctly discriminate between biliary sludge (hyperechoic material without acoustic shadowing) and microlithiasis (echorich calculi of ≤5 mm with acoustic shadowing) as opposed to larger biliary stones, both for location in gallbladder and bile ducts. In an initial attempt to investigate the clinical relevance in a retrospective analysis in 177 confirmed cases in our hospital, there was no difference in severity of AP if caused by sludge, microlithiasis or stones. Conclusion We propose a consensus definition for the localisation, ultrasound morphology and diameter of biliary sludge and microlithiasis as distinct entities. Interestingly, severity of biliary AP was not dependent on the size of concrements warranting prospective randomised studies which treatment options are adequate to prevent recurrence.
Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial
Authors: Antoine Roquilly, Bruno Francois, Olivier Huet, Yoann Launey, Sigismond Lasocki, Emmanuel Weiss, Melanie Petrier, Yannick Hourmant, Marwan Bouras, Karim Lakhal, Cecilia Le Bel, Delphine Flattres Duchaussoy, Laia Fernández-Barat, Adrian Ceccato, Laurent Flet, Alexandra Jobert, Jeremie Poschmann, Veronique Sebille, Fanny Feuillet, Despoina Koulenti, Antoni Torres, Nicolas Grillot, Karim Asehnoune, Alexandre Bourdiol, Dominique Demeure dit latte, Apostolos Armaganidis, Nicolas Nesseler, Philippe Seguin
Journal: Intensive Care Medicine (2023)

We aimed to determine whether interferon gamma-1b prevents hospital-acquired pneumonia in mechanically ventilated patients. In a multicenter, placebo-controlled, randomized trial conducted in 11 European hospitals, we randomly assigned critically ill adults, with one or more acute organ failures, under mechanical ventilation to receive interferon gamma-1b (100 µg every 48 h from day 1 to 9) or placebo (following the same regimen). The primary outcome was a composite of hospital-acquired pneumonia or all-cause mortality on day 28. The planned sample size was 200 with interim safety analyses after enrolling 50 and 100 patients. The study was discontinued after the second safety analysis for potential harm with interferon gamma-1b, and the follow-up was completed in June 2022. Among 109 randomized patients (median age, 57 (41–66) years; 37 (33.9%) women; all included in France), 108 (99%) completed the trial. Twenty-eight days after inclusion, 26 of 55 participants (47.3%) in the interferon-gamma group and 16 of 53 (30.2%) in the placebo group had hospital-acquired pneumonia or died (adjusted hazard ratio (HR) 1.76, 95% confidence interval (CI) 0.94–3.29; P = 0.08). Serious adverse events were reported in 24 of 55 participants (43.6%) in the interferon-gamma group and 17 of 54 (31.5%) in the placebo group (P = 0.19). In an exploratory analysis, we found that hospital-acquired pneumonia developed in a subgroup of patients with decreased CCL17 response to interferon-gamma treatment. Among mechanically ventilated patients with acute organ failure, treatment with interferon gamma-1b compared with placebo did not significantly reduce the incidence of hospital-acquired pneumonia or death on day 28. Furthermore, the trial was discontinued early due to safety concerns about interferon gamma-1b treatment.
Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up
Authors: Thomas Powles, Se Hoon Park, Claudia Caserta, Begoña P. Valderrama, Howard Gurney, Anders Ullén, Yohann Loriot, Srikala S. Sridhar, Cora N. Sternberg, Joaquim Bellmunt, Jeanny B. Aragon-Ching, Jing Wang, Bo Huang, Robert J. Laliberte, Alessandra di Pietro, Petros Grivas
Journal: Journal of Clinical Oncology (2023)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432 ) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC. Here, we report updated data with ≥ 2 years of follow-up in all patients, including OS (primary end point), PFS, safety, and additional novel analyses. Patients were randomly assigned 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). At data cutoff (June 4, 2021), median follow-up was 38.0 months and 39.6 months, respectively; 67 patients (19.5%) had received ≥2 years of avelumab treatment. OS remained longer with avelumab plus BSC versus BSC alone in all patients (hazard ratio, 0.76 [95% CI, 0.63 to 0.91]; 2-sided P = .0036). Investigator-assessed PFS analyses also favored avelumab. Longer-term safety was consistent with previous analyses; no new safety signals were identified with longer treatment duration. In conclusion, longer-term follow-up continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance plus BSC versus BSC alone in patients with aUC. An interactive visualization of data reported in this article is available.